The human fetus is dependent on an adequate supply of zinc in order to achieve normal pre- and postnatal development. Because of its location, the placenta, and in particular, the placental trophoblast, must play a critically important role in the delivery of maternal zinc to the fetus. The major long-term objective of this proposal is to gain some understanding of the cellular mechanism involved in placental transport of maternal zinc to the fetus. In plasma, zinc is mostly found associated with albumin and alpha2M. Therefore, in the first specific aim we propose to use a combination of biochemical and morphological techniques to evaluate the roles of fluid-phase and adsorptive endocytosis in the uptake and processing of alpha2M and albumin. In the second specific aim we will study the uptake and processing of zinc in the form of complexes with alpha2M and albumin and to determine the factors and intracellular compartments involved in the dissociation and subsequent processing of protein-bound zinc. The third specific aim will investigate the kinetics and control of zinc release and attempt to discover the chemical form of the released metal. Together, these three specific aims should provide important new information on the cellular mechanisms involved in zinc uptake and metabolism by trophoblast. In specific aim four we will study the effects of zinc on the control of alpha2M receptor expression since changes in expression could have an effect on intracellular zinc levels and on zinc transport. In the last specific aim we will study the role of metallothionein in trophoblast zinc metabolism. Metallothionein has been implicated in the control of zinc homeostasis in a number of systems. We will examine metallothionein levels during differentiation in vitro as well as measuring rates of metallothionein synthesis and degradation.